Method for breast cancer recurrence prediction under endocrine treatment

Abstract

The present invention relates to methods, kits and systems for the prognosis of the disease outcome of breast cancer, said method comprising: (a) determining in a tumor sample from said patient the RNA expression levels of at least 2 of the following 9 genes: UBE2C, BIRC5, RACGAP1, DHCR7, STC2, AZGP1, RBBP8, IL6ST, and MGP (b) mathematically combining expression level values for the genes of the said set which values were determined in the tumor sample to yield a combined score, wherein said combined score is indicative of a prognosis of said patient; and kits and systems for performing said method.

The invention claimed is: 
     
       1. A method for treating a patient having an estrogen receptor positive and HER2 negative breast tumor, the method comprising:
 determining whether the patient will benefit from cytotoxic chemotherapy by: 
 (1) determining in a sample from the tumor the RNA expression level values of a set of marker genes, the set of marker genes comprising RACGAP1 and at least three of the following genes: UBE2C, BIRC5, DHCR7, STC2, AZGP1, RBBP8, IL6ST, and MGP; 
 (2) combining the expression level values determined in step (1) to yield a test combined score; and 
 administering a treatment regimen comprising a cytotoxic chemotherapy to the patient if the test combined score exceeds a reference combined score, or 
 administering a treatment regimen comprising a non-cytotoxic therapy to the patient if the test combined score does not exceed the reference combined score. 
 
     
     
       2. The method of  claim 1 , wherein the set of marker genes comprises: UBE2C, RACGAP1, DHCR7, STC2, AZGP1, RBBP8, IL6ST, and MGP. 
     
     
       3. The method of  claim 1 , wherein the patient has received endocrine therapy or an endocrine treatment has been prescribed for the patient. 
     
     
       4. The method of  claim 3 , wherein the endocrine therapy comprises tamoxifen or an aromatase inhibitor. 
     
     
       5. The method of  claim 1 , wherein the expression level value is detected as a Messenger-RNA expression level value. 
     
     
       6. The method of  claim 5 , wherein the expression level value is detected by at least one of
 (a) a PCR-based method, 
 (b) a microrarray-based method, or 
 (c) a hybridization-based method. 
 
     
     
       7. The method of  claim 1 , wherein the sample is a formalin-fixed paraffin-embedded sample. 
     
     
       8. The method of  claim 1 , wherein the expression level value of at least one marker gene is determined as a pattern of expression relative to at least one reference gene or to a computed average expression value. 
     
     
       9. The method of  claim 1 , wherein step (1) comprises applying an algorithm to values representative of expression levels of given genes. 
     
     
       10. The method of  claim 9 , wherein the algorithm is a linear combination of the values representative of expression levels of given genes. 
     
     
       11. The method of  claim 10 , wherein at least one of the values representative of expression levels of given genes is multiplied with a coefficient. 
     
     
       12. The method of  claim 1 , wherein step (1) comprises processing information regarding nodal status of the patient. 
     
     
       13. The method of  claim 12 , wherein the information regarding nodal status is a first numerical value if the nodal status is negative, the information is a second numerical value if the nodal status is positive, and the information is either the first numerical value, the second numerical value, or a third numerical value if the nodal status is unknown. 
     
     
       14. The method of  claim 1 , wherein the-non-cytotoxic therapy is an endocrine therapy. 
     
     
       15. The method of  claim 14 , wherein administering the endocrine therapy comprises administration of tamoxifen or derivative thereof. 
     
     
       16. The method of  claim 1 , wherein the set of marker genes comprises RACGAP1 and at least 4 of the following genes: UBE2C, BIRC5, DHCR7, STC2, AZGP1, RBBP8, IL6ST, and MGP. 
     
     
       17. The method of  claim 1 , wherein the set of marker genes comprises RACGAP1 and at least 5 of the following genes: UBE2C, BIRC5, DHCR7, STC2, AZGP1, RBBP8, IL6ST, and MGP. 
     
     
       18. The method of  claim 1 , wherein the set of marker genes comprises RACGAP1 and at least 6 of the following genes: UBE2C, BIRC5, DHCR7, STC2, AZGP1, RBBP8, IL6ST, and MGP. 
     
     
       19. The method of  claim 1 , wherein the set of marker genes comprises UBE2C, BIRC5, RACGAP1, DHCR7, STC2, AZGP1, RBBP8, IL6ST, and MGP. 
     
     
       20. A method for treating a patient having an estrogen receptor positive and HER2 negative breast tumor, the method comprising:
 determining whether the patient will benefit from cytotoxic chemotherapy by: 
 (1) determining in a sample from the tumor the RNA expression level values of a set of marker genes, the set of marker genes comprising RACGAP1 and at least two of the following genes: BIRC5, DHCR7, STC2, AZGP1, RBBP8, IL6ST, and MGP; 
 (2) combining the expression level values determined in step (1) to yield a test combined score; and 
 administering a treatment regimen comprising a cytotoxic chemotherapy to the patient if the test combined score exceeds a reference combined score, or 
 administering a treatment regimen comprising a non-cytotoxic therapy to the patient if the test combined score does not exceed the reference combined score. 
 
     
     
       21. The method of  claim 20 , wherein the patient has received endocrine therapy or an endocrine treatment has been prescribed for the patient. 
     
     
       22. The method of  claim 21 , wherein the endocrine therapy comprises tamoxifen or an aromatase inhibitor. 
     
     
       23. The method of  claim 20 , wherein the expression level value is detected as a Messenger-RNA expression level value and wherein the expression level value is detected by at least one of
 (a) a PCR-based method, 
 (b) a microrarray-based method, or 
 (c) a hybridization-based method. 
 
     
     
       24. The method of  claim 20 , wherein the sample is a formalin-fixed paraffin-embedded sample. 
     
     
       25. The method of  claim 20 , wherein the expression level value of at least one marker gene is determined as a pattern of expression relative to at least one reference gene or to a computed average expression value. 
     
     
       26. The method of  claim 20 , wherein step (1) comprises applying an algorithm to values representative of expression levels of given genes and wherein the algorithm is a linear combination of the values representative of expression levels of given genes. 
     
     
       27. The method of  claim 26 , wherein at least one of the values representative of expression levels of given genes is multiplied with a coefficient. 
     
     
       28. The method of  claim 20 , wherein step (1) comprises processing information regarding nodal status of the patient, wherein the information regarding nodal status is a first numerical value if the nodal status is negative, the information is a second numerical value if the nodal status is positive, and the information is either the first numerical value, the second numerical value, or a third numerical value if the nodal status is unknown. 
     
     
       29. The method of  claim 20 , wherein the-non-cytotoxic therapy is an endocrine therapy. 
     
     
       30. The method of  claim 29 , wherein administering the endocrine therapy comprises administration of tamoxifen or derivative thereof. 
     
     
       31. A method for treating a patient having an estrogen receptor positive and HER2 negative breast tumor, the method comprising:
 determining whether the patient will benefit from cytotoxic chemotherapy by: 
 (1) determining in a sample from the tumor the RNA expression level values of a set of marker genes, the set of marker genes comprising RACGAP1 and at least two of the following genes: UBE2C, DHCR7, STC2, AZGP1, RBBP8, IL6ST, and MGP; 
 (2) combining the expression level values determined in step (1) to yield a test combined score; and 
 administering a treatment regimen comprising a cytotoxic chemotherapy to the patient if the test combined score exceeds a reference combined score, or 
 administering a treatment regimen comprising a non-cytotoxic therapy to the patient if the test combined score does not exceed the reference combined score. 
 
     
     
       32. The method of  claim 31 , wherein the patient has received endocrine therapy or an endocrine treatment has been prescribed for the patient. 
     
     
       33. The method of  claim 32 , wherein the endocrine therapy comprises tamoxifen or an aromatase inhibitor. 
     
     
       34. The method of  claim 31 , wherein the expression level value is detected as a Messenger-RNA expression level value and wherein the expression level value is detected by at least one of
 (a) a PCR-based method, 
 (b) a microrarray-based method, or 
 (c) a hybridization-based method. 
 
     
     
       35. The method of  claim 31 , wherein the sample is a formalin-fixed paraffin-embedded sample. 
     
     
       36. The method of  claim 31 , wherein the expression level value of at least one marker gene is determined as a pattern of expression relative to at least one reference gene or to a computed average expression value. 
     
     
       37. The method of  claim 31 , wherein step (1) comprises applying an algorithm to values representative of expression levels of given genes and wherein the algorithm is a linear combination of the values representative of expression levels of given genes. 
     
     
       38. The method of  claim 37 , wherein at least one of the values representative of expression levels of given genes is multiplied with a coefficient. 
     
     
       39. The method of  claim 31 , wherein step (1) comprises processing information regarding nodal status of the patient, wherein the information regarding nodal status is a first numerical value if the nodal status is negative, the information is a second numerical value if the nodal status is positive, and the information is either the first numerical value, the second numerical value, or a third numerical value if the nodal status is unknown. 
     
     
       40. The method of  claim 31 , wherein the-non-cytotoxic therapy is an endocrine therapy. 
     
     
       41. The method of  claim 40 , wherein administering the endocrine therapy comprises administration of tamoxifen or derivative thereof.